The olfactory organs of the malaria mosquito Anopheles gambiae. (Source: Ray Lab, UC Riverside)Mosquitoes can be the bane of our existence. They not only are nuisance pests, but they also spread dangerous diseases like malaria, dengue fever, West Nile virus and filariasis.

Insights into controlling mosquitoes often focuses on how they are attracted to humans, which is by smelling the carbon dioxide we exhale. From that they can track us down even from a distance. But once they get close to us, mosquitos often steer toward exposed areas of skin such as ankles and feet.

Why does the mosquito change its track and fly towards skin? How does it detect bare skin? What odors from skin does it detect?

New research by a team from the University of California-Riverside (UCR) has shown that an often overlooked mosquito organ, the maxillary palp, plays an important role in mosquito targeting. The work not only has identified the maxillary palp’s role in breath and skin detection, it also has identified compounds that can attract and repel mosquitoes.

“This work identifies an olfactory receptor in mosquitoes that detects both carbon dioxide in our exhaled breath as well as skin odors,” says Anandasankar Ray, an associate professor in the UCR Department of Entomology and the project’s principal investigator. “This important finding enables us to identify other odors that can either block the receptor and reduce the ability of mosquitoes to find us, or identify odors that can activate the receptor and lure mosquitoes closer.”

Specifically, the researchers found that the same receptors in the mosquito’s maxillary palp that detect carbon dioxide are ones that detect skin odors as well. Ray and his team—Genevieve Tauxe, Dyan MacWilliam, Sean Michael Boyle and Tom Guda—reported their findings in the Dec. 5, 2013 issue of Cell.

Until now, which mosquito olfactory neurons were required for attraction to skin odor remained a mystery.  The new finding — that the CO2-sensitive olfactory neuron is also a sensitive detector of human skin — is critical not only for understanding the basis of the mosquito’s host attraction and host preference, but also because it identifies this dual receptor of CO2 and skin-odorants as a key target that could be useful to disrupt host-seeking behavior and aid in the control of disease transmission.

“The maxillary palps have been somewhat ignored in the search for mosquito behavior identifying odors,” said Ray, who has been working in this field since 2009. “This organ now provides a new opportunity to identify odorants that may disrupt the attraction of mosquitoes to humans.”

Anandasankar Ray (Source: L. Duka)Ray said the work focused on a receptor neuron designated cpA, which is an extremely sensitive detector of several skin odorants and is, in fact, far more sensitive to some of these odor molecules as compared to carbon dioxide.

To test whether cpA activation by human odor is important for attraction, the researchers devised a novel chemical-based strategy to shut down the activity of cpA in Aedes aegypti, the dengue-spreading mosquito.  Then they tested the mosquito’s behavior on human foot odor—using a dish of foot odor-laden beads placed in an experimental wind tunnel—and found the mosquito’s attraction to the odor was greatly reduced.

Using an in-house chemical computational method, the researchers screened nearly half a million compounds and identified thousands of predicted ligands. They short-listed 138 compounds based on desirable characteristics such as smell, safety, cost and whether they occurred naturally. Several compounds either inhibited or activated cpA neurons, of which nearly 85 percent were already approved for use as flavor, fragrance or cosmetic agents. Better still, several were pleasant-smelling, such as minty, raspberry, chocolate, etc., increasing their value for use in mosquito control.

Confident that they were on the right track, the researchers then zeroed in on two compounds: ethyl pyruvate, a fruity-scented cpA inhibitor approved as a flavor agent in food; and cyclopentanone, a minty-smelling cpA activator approved as a flavor and fragrance agent. By inhibiting the cpA neuron, ethyl pyruvate was found to substantially reduce the mosquito’s attraction towards a human arm. By activating the cpA neuron, cyclopentanone served as a powerful lure, like CO2, attracting mosquitoes to a trap.

Ray said the method tested affects “about 75 percent of mosquitoes. Additional research is required to improve this level further.” But he is optimistic of the compound’s role in mosquito control.

“Such compounds can play a significant role in the control of mosquito-borne diseases and open up very realistic possibilities of developing ways to use simple, natural, affordable and pleasant odors to prevent mosquitoes from finding humans,” said Ray, who suffered from malaria as a child while growing up in India. “Odors that block this dual-receptor for CO2 and skin odor can be used as a way to mask us from mosquitoes.

“On the other hand, odors that act as attractants can be used to lure mosquitoes away from us into traps,” he added. “These potentially affordable ‘mask’ and ‘pull’ strategies could be used in a complementary manner, offering an ideal solution and much needed relief to people in Africa, Asia and South America—indeed wherever mosquito-borne diseases are endemic.”